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Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches

The biomineral haemozoin, or its synthetic analogue β-haematin (βH), has been the focus of several target-based screens for activity against Plasmodium falciparum parasites. Together with the known βH crystal structure, the availability of this screening data makes the target amenable to both struct...

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Autores principales: Amod, Leah, Mohunlal, Roxanne, Teixeira, Nicole, Egan, Timothy J., Wicht, Kathryn J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9929333/
https://www.ncbi.nlm.nih.gov/pubmed/36788274
http://dx.doi.org/10.1038/s41598-023-29273-w
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author Amod, Leah
Mohunlal, Roxanne
Teixeira, Nicole
Egan, Timothy J.
Wicht, Kathryn J.
author_facet Amod, Leah
Mohunlal, Roxanne
Teixeira, Nicole
Egan, Timothy J.
Wicht, Kathryn J.
author_sort Amod, Leah
collection PubMed
description The biomineral haemozoin, or its synthetic analogue β-haematin (βH), has been the focus of several target-based screens for activity against Plasmodium falciparum parasites. Together with the known βH crystal structure, the availability of this screening data makes the target amenable to both structure-based and ligand-based virtual screening. In this study, molecular docking and machine learning techniques, including Bayesian and support vector machine classifiers, were used in sequence to screen the in silico ChemDiv 300k Representative Compounds library for inhibitors of βH with retained activity against P. falciparum. We commercially obtained and tested a prioritised set of inhibitors and identified the coumarin and iminodipyridinopyrimidine chemotypes as potent in vitro inhibitors of βH and whole cell parasite growth.
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spelling pubmed-99293332023-02-16 Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches Amod, Leah Mohunlal, Roxanne Teixeira, Nicole Egan, Timothy J. Wicht, Kathryn J. Sci Rep Article The biomineral haemozoin, or its synthetic analogue β-haematin (βH), has been the focus of several target-based screens for activity against Plasmodium falciparum parasites. Together with the known βH crystal structure, the availability of this screening data makes the target amenable to both structure-based and ligand-based virtual screening. In this study, molecular docking and machine learning techniques, including Bayesian and support vector machine classifiers, were used in sequence to screen the in silico ChemDiv 300k Representative Compounds library for inhibitors of βH with retained activity against P. falciparum. We commercially obtained and tested a prioritised set of inhibitors and identified the coumarin and iminodipyridinopyrimidine chemotypes as potent in vitro inhibitors of βH and whole cell parasite growth. Nature Publishing Group UK 2023-02-14 /pmc/articles/PMC9929333/ /pubmed/36788274 http://dx.doi.org/10.1038/s41598-023-29273-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Amod, Leah
Mohunlal, Roxanne
Teixeira, Nicole
Egan, Timothy J.
Wicht, Kathryn J.
Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches
title Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches
title_full Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches
title_fullStr Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches
title_full_unstemmed Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches
title_short Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches
title_sort identifying inhibitors of β-haematin formation with activity against chloroquine-resistant plasmodium falciparum malaria parasites via virtual screening approaches
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9929333/
https://www.ncbi.nlm.nih.gov/pubmed/36788274
http://dx.doi.org/10.1038/s41598-023-29273-w
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